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Community-acquired respiratory syncytial virus and parainfluenza virus infections after hematopoietic stem cell transplantation: the Fred Hutchinson Cancer Research Center experience.

Community respiratory viruses (CRVs) are an important cause of morbidity and mortality among recipients of hematopoietic stem cell transplants (HSCT). At the Fred Hutchinson Cancer Research Center, respiratory syncytial virus (RSV) and parainfluenza virus (PIV) infections in HSCT recipients have been studied intensively for more than a decade. Over time, mortality from these infections has declined as the approach to diagnosis has become more aggressive and more stringent preventive measures have been instituted. However, mortality among HSCT recipients with RSV or PIV pneumonia remains high. Uncontrolled studies at our center suggest that prompt therapy with aerosolized ribavirin has reduced mortality from RSV pneumonia but does not appear to affect the course of established PIV pneumonia. Two controlled clinical trials of ribavirin therapy for RSV infection in HSCT recipients are in progress.

Clinical Trials as Topic↗

Prior infection by respiratory syncytial virus or parainfluenza viruses augments virus-specific IgG responses induced by the measles/mumps/rubella vaccine.

We found previously that immunizing cyclophosphamide-treated mice with one Paramyxoviridae virus mixed with dimethyl dioctadecyl ammonium bromide induces T cells which apparently also recognize other Paramyxoviridae viruses. This finding and the fact that respiratory syncytial virus (RSV) and parainfluenza viruses (PIVs) infect children early in life led us to ask if prior RSV or PIV infections influence the antibody response to measles and mumps vaccine viruses. Detection of virus-specific IgG in serum specimens collected randomly or at defined times after measles/mumps/rubella (MMR) vaccination was done with solid-phase enzyme immunoassays. The antibody-binding data obtained were converted to serum antibody titers by an immunoassay curve-fitting computer program. Prior infection by RSV and PIVs correlated with an augmented IgG response not only to measles and mumps virus, but also to rubella virus. Furthermore, the augmentation was greater for responders below the median response. These data show that common early childhood viral infections can influence immunity induced by the MMR vaccine.

Antibodies, Viral↗

Pathogenesis of severe acute respiratory infections in the developing world: respiratory syncytial virus and parainfluenza viruses.

Respiratory syncytial virus (RSV) and parainfluenza viruses (PIVs) are the most frequently isolated pathogens in infants and children with acute lower respiratory infection (LRI) in the developed world. Less information is available about their importance in LRI in the developing world, but they are probably important there also. The pathogenesis of viral bronchiolitis and pneumonia involves inoculation and early replication in the upper respiratory tract, followed by aspiration into the lower respiratory tract when both the mucosal and systemic immune systems are involved in a specific response. Both disease and recovery reflect processes of viral replication (with attendant cellular destruction) and of immune response (with attendant direct cellular destruction and release of pathogenic, along with beneficial, mediators). Factors predisposing to bacterial superinfection are poorly understood except in animal models. Conditions leading to heightened susceptibility to severe disease in the developed world are particularly common in the developing world. Increasing information on RSV and PIV infections in the developing world will likely point to their importance. Strategies for prevention of severe illnesses due to these viruses will follow from concepts elucidated through animal models and studies of infants in the developed world.

Acute Disease↗

Respiratory syncytial virus and parainfluenza virus infections in the immunocompromised host.

Respiratory syncytial virus (RSV) and parainfluenza virus (PIV) are common causes of respiratory infections in immunocompetent children under the age of 6 years. These viruses belong to a family of enveloped single-stranded RNA viruses, the paramyxoviruses. The clinical manifestations in the normal host range from mild illness to severe croup, bronchiolitis, and pneumonia. After the age of 6 years, reinfections occur, but are characterized by diminishing frequency and severity. In contrast to the normal adult host, severe lower respiratory tract infection can occur in immunocompromised adults as well as children, with significant morbidity and mortality. Similar to the normal host, infection with RSV occurs in epidemics in the winter and spring, while PIV occurs throughout the year. Immunocompromised hosts often have upper respiratory tract symptoms similar to those experienced by normal hosts, as well as a higher incidence of lower respiratory tract symptoms and sinusitis. Lower respiratory tract infection can lead to respiratory failure and death, especially in bone marrow transplant recipients. The diagnosis of RSV and PIV depends on the analysis of specimens obtained from the respiratory tract. Rapid diagnostic tests are readily available for RSV and are less widely used for some of the PIV serotypes. Primary cultures are used for both viruses, but take several days to yield a positive result. Ribavirin, a broad-spectrum antiviral agent, is effective against RSV and PIV in vitro. Clinical trials have shown ribavirin to be of benefit in treating infants infected with RSV. However, clinical trials in immunocompromised patients infected with RSV or PIV have not been carried out. Since infection with RSV and PIV can be severe and life-threatening and treatment with ribavirin is relatively benign, it seems warranted to treat immunocompromised patients infected with RSV or PIV with ribavirin until otherwise proven unwarranted.

Antiviral Agents↗

Standardization of enzyme-linked immunosorbent assays (ELISAs) for quantitative estimation of antibodies specific for infectious bovine rhinotracheitis virus, respiratory syncytial virus, parainfluenza-3 virus, and bovine viral diarrhea virus.

Commercial enzyme-linked immunosorbent assays (ELISAs) for detection of serum antibodies to bovine viral diarrhea virus (BVDV), parainfluenza-3 virus (PI3V), respiratory syncytial virus (RSV), and infectious bovine rhinotracheitis virus (IBRV) were standardized to give a quantitative result when testing was performed at a single optimum dilution. For each test, serum samples were titrated and their end point titers calculated by an algebraic method directly from a plot of each titration series and also from a regression line fitted to this plot. The corrected optical density (COD) of each sample when tested at dilutions of 1/25, 1/50, and 1/100 was expressed as a percentage of the COD of a positive reference serum included on each plate, this value was the sample/positive (S/P) ratio. For each test, the linear relationship between the S/P ratio obtained at a dilution of 1/25, 1/50, and 1/100 and the end point titer calculated by each method was determined. In each case, the best linear relationship existed when samples were tested at a dilution of 1/100 (r = 0.973 for BVDV, 0.962 for PI3V, 0.961 for RSV, 0.947 for IBRV). From the equation of these lines, an increase in the S/P ratio between acute and convalescent serum samples of 31%, 23%, 21%, and 35% would correspond to a 4-fold rise in ELISA titer to BVDV, PI3V, RSV, and IBRV, respectively. ELISA titers calculated from S/P ratios at 1/100 were significantly related to virus neutralization titers to BVDV, RSV, and IBRV and to hemagglutination inhibition titers to PI3V (P < < 0.001 in all cases). Samples with low S/P ratios had the greatest intraassay and interassay variation. Intraassay reproducibility ranged from 3.5% to 22.3% (coefficient of variation), with a median value of 9.5%. Interassay reproducibility was lower, ranging from 6.0% to 50.6%, with a median of 17.4%.

Animals↗

Evaluation of a single dilution ELISA system for detection of seroconversion to bovine viral diarrhea virus, bovine respiratory syncytial virus, parainfluenza-3 virus, and infectious bovine rhinotracheitis virus: comparison with testing by virus neutralization and hemagglutination inhibition.

A single-dilution quantitative enzyme-linked immunosorbent assay (ELISA) system, based on commercial ELISA kits, for the simultaneous detection of seroconversion to bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus (BRSV), parainfluenza-3 virus (PI3V), and infectious bovine rhinotracheitis virus (IBRV) was evaluated by testing acute and convalescent serum pairs from 564 cattle in 145 outbreaks of respiratory disease. Seroconversion to BVDV, BRSV, PI3V and IBRV was detected in 8.0%, 19.0%, 13.7%, and 7.4%, respectively, of serum pairs tested. Seroconversion was detected in 60.7% of herds and 34.6% of animals tested. Infection with 2 or more viruses was found in 46.6% of these herds and in 27.2% of these animals. The majority of BVDV infections (62%) were associated with other virus infections, suggesting that BVDV may potentiate infection with other agents rather than being a primary pathogen of the respiratory tract. The results were compared with those obtained by virus neutralization and hemagglutination inhibition testing, and the sensitivity, specificity, and overall correlation were calculated. Sensitivities of 92%, 95%, 100%, and 100% were obtained for BVDV, BRSV, PI3V, and IBRV, respectively. The corresponding specificity values were 89%, 92%, 86%, and 91%. The overall correlation for each virus was 90%, 93%, 90%, and 93%, respectively. These results demonstrate that this ELISA system may be used successfully to detect seroconversion in serum pairs, highlight the frequency of multiple viral infections in outbreaks of respiratory disease, and provide further evidence of an immunosuppressive role for BVDV infections.

Animals↗

Serologic profile of children in a Mexican highland community: prevalence of complement-fixing antibodies to Mycoplasma pneumoniae, respiratory syncytial virus and parainfluenza viruses.

The study investigated the prevalence of antibodies to five leading agents of childhood respiratory disease in the county of Huixquilucan, Mexico. Tests of sera from a random sample of children between 3 months and 18 years of age confirmed serologically the presence of Mycoplasma pneumoniae, respiratory syncytial (RS) virus and parainfluenza 1, 2 and 3 viruses in this relatively isolated highland community. Highest overall antibody frequency of 64.2% was seen for parainfluenza 3, and antibody to this virus was acquired early in life. Antibody to M. pneumoniae was least prevalent among children surveyed; this rate was 15.5% overall. This was only slightly below the prevalence rates for antibodies to RS virus and parainfluenza 1 and 2 viruses, which had intermediate frequency rates of 23%, 32%, and 22.9%, respectively. The relatively low prevalence of antibody to RS virus was unexpected. Differences in prevalence rates in regard to location of residence or family size were insignificant. Statistically significant differences in age-specific antibody prevalence rates in respect to sex were noted only for the 5- to 9-year-old group to M. pneumoniae and to parainfluenza 3.

Adolescent↗

The association between serological titers in infectious bovine rhinotracheitis virus, bovine virus diarrhea virus, parainfluenza-3 virus, respiratory syncytial virus and treatment for respiratory disease in Ontario feedlot calves.

A seroepidemiological study of the association between antibody titers to infectious bovine rhinotracheitis, parainfluenza-3, bovine virus diarrhea and bovine respiratory syncytial viruses, and treatment for bovine respiratory disease was conducted. A total of 322 calves from five different groups were bled on arrival, then one month later all cases (cattle treated for bovine respiratory disease) were rebled together with an equal number of controls (cattle not treated for any disease). Titers to these viruses varied significantly from group to group. Based on seroconversion, infectious bovine rhinotracheitis virus was active in 4.4%, bovine virus diarrhea virus in 24%, parainfluenza-3 virus in 69.5% and bovine respiratory syncytial virus in 71.3% of the cattle. Cattle with low titers to infectious bovine rhinotracheitis and/or bovine respiratory syncytial viruses on arrival, were at increased risk of subsequent treatment for bovine respiratory disease. Treated cattle also had significantly greater increases to parainfluenza-3 and/or bovine virus diarrhea viruses than control calves. Treatment rates varied considerably from group to group and were not strongly correlated with weight gain in the postarrival period.

Animals↗

Antibody responses by cattle after vaccination with commercial viral vaccines containing bovine herpesvirus-1, bovine viral diarrhea virus, parainfluenza-3 virus, and bovine respiratory syncytial virus immunogens and subsequent revaccination at day 140.

Calves were vaccinated with four different commercial viral vaccines containing bovine herpesvirus-1 (BHV-1), bovine viral diarrhea (BVDV), parainfluenza-3 virus (PI-3V), and bovine respiratory syncytial virus (BRSV) immunogens. For the initial vaccination certain vaccines were given twice (days 0 and 28), whereas other vaccines were given on day 0. The calves received another injection on day 140 with the vaccine originally given on day 0. The sera were collected at days 0, 7, 14, 21, 28, 42, 56, 84, 112, 140, 154, 168, and 196 and assayed for viral neutralizing antibodies. The calves were seronegative to BHV-1, BVDV, and BRSV at the onset of the experiment; however, the calves were PI-3V antibody positive due to prior active infection. The commercial vaccines were: (I) inactivated; (II) modified live virus (MLV); (III) combination of chemically altered live virus, MLV, and inactivated virus; and (IV) combination of inactivated and MLV. Among the vaccine groups there were differences in onset and duration of antibodies as measured by geometric mean titers to each immunogen in postvaccination collection dates compared to day 0 titers; and likewise compared to day 140 titers after revaccination at day 140. There were also differences in antibody titers to the various viruses among the vaccine groups on specific collection dates. All four vaccines induced increased BHV-1 antibodies by day 14 after the initial injection. The antibody titers induced by MLV BHV-1 and the chemically altered BHV-1 vaccines had greater duration than those induced by the inactivated vaccine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

Serological titers to bovine herpesvirus 1, bovine viral diarrhea virus, parainfluenza 3 virus, bovine respiratory syncytial virus and Pasteurella haemolytica in feedlot calves with respiratory disease: associations with bacteriological and pulmonary cytological variables.

Acute and convalescent serum samples were taken from 59 calves with signs of respiratory disease (cases) and 60 clinically normal animals (controls) during their first month in the feedlot. Sera were analyzed for antibodies to bovine parainfluenza 3 (PI3) virus by hemagglutination inhibition, to bovine viral diarrhea (BVD) virus, bovine respiratory syncytial (BRS) virus and bovine herpesvirus 1 (BHV1) by virus neutralization, and to Pasteurella haemolytica by indirect agglutination (PhIA) and cytotoxin neutralization (PhCN) tests. There was minimal evidence of serological activity to BHV1. Serological activity to the other agents occurred commonly and the prevalence of acute titers and their mean values was similar in case and control groups. Mean convalescent PI3 and P. haemolytica (PhIA) titers were higher in controls than cases (p < 0.01) but, otherwise, convalescent titers did not differ between groups. The incidence of seroconversion was similar in both groups for all agents except for PI3 virus which was more frequent in controls than cases (p < 0.0001). There was a positive association between PhIA and CN seroconversion and isolation of P. haemolytica from bronchoalveolar lavage (BAL) fluid (p < 0.1). The measure of agreement (kappa) between seroconversion with the P. haemolytica PhIA and PhCN tests was 0.51. Bacteriological and cytological evaluations of the respiratory tract were made using BAL. No associations were evident between serological titers and pulmonary cytology. A multivariate logistic analysis was used to evaluate associations between disease status and serological, bacteriological and cytological data. Cases were positively associated with the presence of neutrophils and Pasteurella multocida in BAL fluid and negatively associated with PI3 virus and PhIA seroconversion.

Acute Disease↗

Protection against respiratory disease in calves induced by vaccines containing respiratory syncytial virus, parainfluenza type 3 virus, Mycoplasma bovis and M dispar.

A field trial to assess the ability of two vaccines to protect calves against respiratory disease was carried out on a large beef rearing unit in southern England over the two winters of 1983 to 1984 and 1984 to 1985. A quadrivalent vaccine containing the killed antigens of respiratory syncytial virus, parainfluenza virus type 3, Mycoplasma bovis and M dispar or a vaccine containing only the respiratory syncytial virus component were inoculated into 246 and 245 calves, respectively; 245 calves remained as unvaccinated controls. The calves were reared in seven batches and outbreaks of disease occurred in five; significant protection was achieved in the four batches in which disease was associated with respiratory syncytial virus and M bovis infection, together or independently. The death rate from pneumonia was 9 per cent in the control group, 2 per cent in the calves inoculated with the quadrivalent vaccine (P less than 0.001), a protection rate of 77 per cent, and 3 per cent in the calves inoculated with the respiratory syncytial virus vaccine (P less than 0.01), a protection rate of 68 per cent. The proportion of calves receiving treatment for respiratory disease was 38 per cent in the control group, 25 per cent in the calves inoculated with the quadrivalent vaccine (P less than 0.001) and 27 per cent in the calves inoculated with the respiratory syncytial virus vaccine (P less than 0.01). The results show that protection against respiratory disease can be achieved by parenteral vaccination of calves with the appropriate inactivated microorganisms.

Animals↗

Expression of the surface glycoproteins of human parainfluenza virus type 3 by bovine parainfluenza virus type 3, a novel attenuated virus vaccine vector.

Bovine parainfluenza virus type 3 (bPIV3) is being evaluated as an intranasal vaccine for protection against human PIV3 (hPIV3). In young infants, the bPIV3 vaccine appears to be infectious, attenuated, immunogenic, and genetically stable, which are desirable characteristics for an RNA virus vector. To test the potential of the bPIV3 vaccine strain as a vector, an infectious DNA clone of bPIV3 was assembled and recombinant bPIV3 (r-bPIV3) was rescued. r-bPIV3 displayed a temperature-sensitive phenotype for growth in tissue culture at 39 degrees C and was attenuated in the lungs of Syrian golden hamsters. In order to test whether r-bPIV3 could serve as a vector, the fusion and hemagglutinin-neuraminidase genes of bPIV3 were replaced with those of hPIV3. The resulting bovine/human PIV3 was temperature sensitive for growth in Vero cells at 37 degrees C. The replication of bovine/human PIV3 was also restricted in the lungs of hamsters, albeit not as severely as was observed for r-bPIV3. Despite the attenuation phenotypes observed for r-bPIV3 and bovine/human PIV3, both of these viruses protected hamsters completely upon challenge with hPIV3. In summary, bPIV3 was shown to function as a virus vector that may be especially suitable for vaccination of infants and children against PIV3 and other viruses.

Animals↗

In vitro antiviral efficacy of ribavirin against feline calicivirus, feline viral rhinotracheitis virus, and canine parainfluenza virus.

Ribavirin had marked in vitro activity against feline calcivirus, strain 255, and canine parainfluenza virus, but showed only slight antiviral effect on feline viral rhinotracheitis virus. Antiviral activity was manifested by partial to complete suppression of viral cytopathic effect and of viral replication, depending on concentration of ribavirin in the culture medium and dosage of viral inoculum. Concentrations of ribavirin as small as 3.2 microgram/ml and 1.0 microgram/ml showed some activity against feline calcivirus and canine parainfluenza virus, respectively.

Animals↗